CN108610322B - Preparation method of R-glyceraldehyde acetonide - Google Patents
Preparation method of R-glyceraldehyde acetonide Download PDFInfo
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- CN108610322B CN108610322B CN201810363250.XA CN201810363250A CN108610322B CN 108610322 B CN108610322 B CN 108610322B CN 201810363250 A CN201810363250 A CN 201810363250A CN 108610322 B CN108610322 B CN 108610322B
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- C07—ORGANIC CHEMISTRY
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention relates to a preparation method of R-glyceraldehyde acetonide, belonging to the technical field of synthesis of pharmaceutical intermediates. In order to solve the problems of high cost and low yield of the existing route, the preparation method of R-glyceraldehyde acetonide is provided, and the method comprises the step of carrying out oxidation reaction on diacetone-D-mannitol under the action of hypochlorite in a solvent system of a water-insoluble organic solvent and water in the coexistence of TEMPO and a crown ether catalyst to convert the diacetone-D-glyceraldehyde acetonide into the R-glyceraldehyde acetonide. The method has the advantages of short reaction route and high conversion rate, can realize the effects of high yield and high purity, is simple to operate, and is beneficial to large-scale industrial production.
Description
Technical Field
The invention relates to a preparation method of R-glyceraldehyde acetonide, belonging to the technical field of synthesis of pharmaceutical intermediates.
Background
R-glyceraldehyde acetonide is used as an intermediate of gemcitabine, and the prior art is synthesized by oxidizing diacetone-D-mannitol with sodium periodate, wherein the sodium periodate is expensive and difficult to recover, and the obtained product has low yield and purity and is not suitable for industrial production; the diacetone-D-mannitol is synthesized by oxidizing lead tetraacetate, wherein the lead tetraacetate is toxic and pollutes the environment, and the obtained product has low yield and purity and is not suitable for industrial production; the (R) -epoxy chloropropane is used as a raw material for synthesis, the reaction step is long, the operation difficulty is high, the yield of the obtained product is low, and the method is not suitable for industrial production; 4-methoxybenzoyl chloride is used as a raw material, potassium osmate which is an expensive and toxic reagent is used in the reaction, the reaction step is long, the operation difficulty is large, the yield of the obtained product is low, and the method is not suitable for industrial production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of R-glyceraldehyde acetonide, and solves the problem of how to provide a novel process with low raw material cost, high product yield and short route.
The invention aims to realize the following technical scheme, and the preparation method of the R-glyceraldehyde acetonide is characterized by comprising the following steps of:
in the coexistence of TEMPO and crown ether catalyst, the diacetone-D-mannitol is oxidized under the action of hypochlorite to be converted into R-glyceraldehyde acetonide in a solvent system of water-insoluble organic solvent and water.
Under the combined action of TEMPO (also called tetramethyl piperidine nitrogen oxide) and a crown ether catalyst, raw material diacetone-D-mannitol in an organic phase and hypochlorite in a water phase can be fully contacted, so that the effective conversion of the raw material diacetone-D-mannitol is realized, sodium periodate and other oxidants which are difficult to recover and expensive are not needed, and the cost is favorably reduced. The adopted raw materials of diacetone-D-mannitol and products are dissolved in an organic phase, hypochlorite is a water-soluble salt, and a catalytic system adopting TEMPO and a crown ether catalyst is combined, so that the raw materials and the hypochlorite are subjected to reaction in a two-phase system, the reaction is facilitated, the reaction only needs to be carried out in one step, and the method has the advantages of short reaction route, effective conversion, high conversion efficiency, high product yield and reaction time shortening; the solvent system between the water-insoluble organic solvent and the water can be a mixed solvent system directly adopting the water-insoluble organic solvent and the water, or can be a form system which firstly dissolves the diacetone-D-mannitol in the water-insoluble organic solvent and then adds the hypochlorite aqueous solution; meanwhile, the invention can not adopt additional acid or alkali for treatment, thus being more beneficial to reducing environmental pollution and realizing the advantage of environmental friendliness; meanwhile, as the invention adopts a two-phase reaction system, the recovery or destruction treatment of the oxidant is not needed after the reaction is finished, and only the layering removal of the water phase is needed, thus having the advantage of simple operation and being more beneficial to the industrial production.
In the above process for producing R-glyceraldehyde acetonide, preferably, the crown ether catalyst is selected from the group consisting of 18-crown-6-ether and 15-crown-5-ether. The raw materials in the organic phase can be more fully contacted with hypochlorite in the water phase, the conversion rate of the raw materials is improved, the reaction can be accelerated, and the effects of improving the reaction efficiency and the high yield are achieved; at the same time, these raw materials also have the advantage of low cost.
In the above-mentioned process for the preparation of R-glyceraldehyde acetonide, the TEMPO and crown ether catalysts are used in such an amount that the reaction can be carried out in a catalytic amount. But for the purpose of better enabling the reaction to be carried out efficiently and enabling the reaction to have higher yield and purity, the crown ether is preferably added in an amount of 1 to 3 wt% of the amount of diacetone-D-mannitol; the adding amount of TEMPO is 1.5-5 wt% of the amount of diacetone-D-mannitol. Can ensure that TEMPO and crown ether have better synergistic action and is beneficial to improving the yield and the purity of the product.
In the above-mentioned process for producing R-glyceraldehyde acetonide, it is generally preferable that the hypochlorite is in the form of an aqueous solution thereof, so that the reaction can be carried out more gently, and for example, an alkali metal hypochlorite or an alkaline earth metal hypochlorite can be used in the form of an aqueous solution thereof. Preferably, the hypochlorite is selected from sodium hypochlorite or calcium hypochlorite. Has the advantages of easily available raw materials and low cost.
In the above process for producing R-glyceraldehyde acetonide, the water-insoluble organic solvent is preferably selected from dichloromethane or ethyl acetate.
In the above-mentioned process for producing R-glyceraldehyde acetonide, the temperature of the oxidation reaction may be usually such that the reaction proceeds. Preferably, the temperature of the oxidation reaction is 35 ℃ or lower. The method is basically carried out at a lower temperature, thereby being beneficial to reducing the generation of byproducts and improving the utilization rate of raw materials, so that the obtained product has the effects of high yield and high purity. As a further preferable mode, the hypochlorite is prepared into a corresponding hypochlorite aqueous solution in advance, and the temperature of the oxidation reaction is 10 ℃ to 25 ℃. The hypochlorite aqueous solution can be added in a dropwise manner, so that the reaction is milder, the by-products can be further reduced, and the purity and quality requirements of the product can be improved.
The specific reaction process of the preparation method of R-glyceraldehyde acetonide of the present invention can be represented by the following reaction equation:
in summary, compared with the prior art, the invention has the following advantages:
1. the method has the advantages that the raw material diacetone-D-mannitol can be effectively converted into a product by adopting a two-phase solvent system under the combined action of TEMPO and a crown ether catalyst, the method has the advantages of short reaction route and high conversion rate, the effects of high yield and high purity can be realized, and the separation purpose can be achieved by directly layering and removing the water phase subsequently after the two-phase solvent system is adopted, so that the method has the advantage of simple operation and is beneficial to large-scale industrial production.
2. The adopted raw materials of diacetone-D-mannitol, hypochlorite and the selected catalyst system have the advantages of easily obtained raw materials and low cost, and the reaction route can effectively reduce the generation of byproducts and realize the effects of high yield and high purity.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
Adding 220g of dichloromethane, 23g of diacetone-D-mannitol, 0.23g of 18-crown-6-ether and 0.4g of TEMPO into a clean reactor in sequence, stirring and mixing uniformly, slowly cooling to 10 ℃, starting to dropwise add 72g of sodium hypochlorite aqueous solution with the mass percent of 10 wt%, controlling the temperature of a reaction system to be below 15 ℃ in the dropwise adding process, continuing to react after dropwise adding is finished, keeping the temperature at 30-32 ℃ for oxidation reaction for 1h, standing and layering after the reaction is finished, removing a water layer, washing a collected organic layer once with 50g of water, layering to remove the water layer, adding 20g of anhydrous sodium sulfate into the collected organic layer, stirring and drying for 30min, performing suction filtration, collecting filtrate, concentrating the filtrate to remove the solvent, drying an obtained wet aldehyde condensate under reduced pressure to obtain 22.1g of a dry product R-glycerol acetone, the yield was 97%, and the gas phase content was 99.2%.
Example 2
Adding 300g of dichloromethane, 23g of diacetone-D-mannitol, 0.4g of 18-crown-6-ether and 0.6g of TEMPO into a clean reactor in sequence, stirring and mixing uniformly, slowly cooling to 15 ℃, starting to dropwise add 80g of sodium hypochlorite aqueous solution with the mass percent of 10 wt%, controlling the temperature of a reaction system to be below 15 ℃ in the dropwise adding process, continuing to react after dropwise adding is finished, keeping the temperature at 20-25 ℃ for oxidation reaction for 1.5h, standing, layering, removing a water layer, washing a collected organic layer once with 50g of water, layering to remove the water layer, adding 20g of anhydrous sodium sulfate into the collected organic layer, stirring, drying for 30min, carrying out suction filtration, collecting filtrate, carrying out reduced pressure concentration on the filtrate to remove the solvent, drying an obtained wet product to obtain 22g of dry product R-glyceraldehyde acetone, the yield was 96.5% and the gas phase content was 99.4%.
Example 3
Adding 200g of ethyl acetate, 23g of diacetone-D-mannitol, 0.6g of 15-crown-5-ether and 0.5g of TEMPO into a clean reactor in sequence, stirring and mixing uniformly, slowly cooling to 5 ℃, starting to dropwise add 140g of a 10 wt% calcium hypochlorite aqueous solution, controlling the temperature of a reaction system below 5 ℃ in the dropwise adding process, continuing to react after dropwise adding is finished, keeping the temperature at 5-10 ℃ for oxidation reaction for 1.5h, standing and layering after the reaction is finished, removing a water layer, washing a collected organic layer once with 50g of water, layering to remove the water layer, adding 20g of anhydrous sodium sulfate into the collected organic layer, stirring and drying for 30min, performing suction filtration, collecting filtrate, performing reduced pressure concentration on the filtrate to remove a solvent, drying an obtained wet product to obtain 22.3g of dry product R-glyceraldehyde acetone, the yield was 97.9%, and the gas phase content was 99.5%.
Example 4
Adding 200g of ethyl acetate, 23g of diacetone-D-mannitol, 0.4g of 18-crown-6-ether and 1.1g of TEMPO into a clean reactor in sequence, stirring and mixing uniformly, slowly cooling to 10 ℃, starting to dropwise add 160g of a 10 wt% calcium hypochlorite aqueous solution, controlling the temperature of a reaction system to be below 15 ℃ in the dropwise adding process, continuing to react after dropwise adding is finished, keeping the temperature at 10-15 ℃ for oxidation reaction for 1.0h, standing and layering after the reaction is finished, removing a water layer, washing a collected organic layer once with 50g of water, layering to remove the water layer, adding 20g of sodium sulfate into the collected organic layer, stirring and drying for 30min, performing suction filtration, collecting filtrate, performing reduced pressure concentration on the filtrate to remove a solvent, drying an obtained wet product to obtain 22.2g of dry product R-glyceraldehyde acetone, the yield was 97.4% and the gas phase content was 99.4%.
Example 5
Adding 200g of ethyl acetate, 23g of diacetone-D-mannitol, 0.69g of 15-crown-5-ether and 0.8g of TEMPO into a clean reactor in sequence, stirring and mixing uniformly, slowly cooling to 10 ℃, starting to dropwise add 100g of 10 wt% potassium hypochlorite aqueous solution, controlling the temperature of a reaction system below 10 ℃ in the dropwise adding process, continuing to react after dropwise adding is finished, keeping the temperature at 5-10 ℃ for oxidation reaction for 1.5h, standing and layering after the reaction is finished, removing a water layer, washing a collected organic layer once with 50g of water, layering to remove the water layer, adding 20g of sodium sulfate into the collected organic layer, stirring and drying for 30min, carrying out suction filtration, collecting filtrate, carrying out reduced pressure concentration on the filtrate to remove a solvent, drying an obtained wet product to obtain 21.9g of dry R-glyceraldehyde acetone, the yield was 96.2% and the gas phase content was 99.3%.
Comparative example 1
To illustrate the effect of the crown ethers of the present invention on the reaction, this comparative example was specifically conducted without adding the corresponding crown ethers.
Adding 200g of ethyl acetate, 23g of diacetone-D-mannitol and 0.8g of TEMPO into a clean reactor in sequence, stirring and mixing uniformly, slowly cooling to 10 ℃, starting to dropwise add 80g of sodium hypochlorite aqueous solution with the mass percent of 10 wt%, controlling the temperature of a reaction system to be below 10 ℃ in the dropwise adding process, continuing to react after dropwise adding is finished to ensure that the temperature is kept at 5-10 ℃ for oxidation reaction for 1.5h, detecting that raw materials are not completely reacted, continuing to react for 1.5h, namely, corresponding to the total reaction time of two times being 3h, directly standing and layering after the reaction is finished, removing a water layer, washing the collected organic layer once with 50g of water, layering to remove the water layer, adding 20g of anhydrous sodium sulfate into the collected organic layer, stirring and drying for 30min, performing suction filtration, collecting filtrate, concentrating the filtrate under reduced pressure to remove a solvent, after the obtained wet product was dried, 16.3g of a dry product of R-glyceraldehyde acetonide was obtained, the yield was 71.5%, and the gas phase content was 97.5%.
Comparative example 2
To illustrate the effect of the crown ether of the present invention on the reaction, this comparative example was specifically conducted by using sodium bromide instead of the crown ether.
Adding 200g of ethyl acetate, 23g of diacetone-D-mannitol, 0.4g of sodium bromide and 0.8g of TEMPO into a clean reactor in sequence, stirring and mixing uniformly, slowly cooling to 10 ℃, starting to dropwise add 80g of sodium hypochlorite aqueous solution with the mass percent of 10 wt%, controlling the temperature of a reaction system to be below 10 ℃ in the dropwise adding process, continuing to react after dropwise adding is finished, keeping the temperature at 5-10 ℃ for oxidation reaction for 3.0h, directly standing and layering after the reaction is finished, removing a water layer, washing a collected organic layer once with 50g of water, layering to remove the water layer, adding 20g of anhydrous sodium sulfate into the collected organic layer, stirring and drying for 30min, carrying out suction filtration, collecting filtrate, carrying out reduced pressure concentration on the filtrate to remove the solvent, drying the obtained wet product to obtain 16.8g of dry product R-glyceraldehyde acetone, the yield was 73.7% and the gas phase content was 97.2%.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (6)
1. A preparation method of R-glyceraldehyde acetonide is characterized by comprising the following steps:
in the coexistence of a catalytic amount of TEMPO and a crown ether catalyst, in a solvent system of a water-insoluble organic solvent and water, diacetone-D-mannitol is subjected to oxidation reaction under the action of hypochlorite to be converted into R-glyceraldehyde acetonide; the water-insoluble organic solvent can dissolve diacetone-D-mannitol; the crown ether catalyst is selected from 18-crown-6-ether or 15-crown-5-ether.
2. The method for preparing R-glyceraldehyde acetonide according to claim 1, wherein the crown ether is added in an amount of 1 to 3 wt% of the amount of diacetone-D-mannitol; the adding amount of TEMPO is 1.5-5 wt% of the amount of diacetone-D-mannitol.
3. The method according to claim 1, wherein said hypochlorite is selected from sodium hypochlorite and calcium hypochlorite.
4. The process for producing R-glyceraldehyde acetonide according to any one of claims 1 to 3, wherein the water-insoluble organic solvent is selected from dichloromethane or ethyl acetate.
5. The process for producing R-glyceraldehyde acetonide according to any one of claims 1 to 3, wherein the oxidation reaction is carried out at a temperature of 35 ℃ or lower.
6. The process for the production of R-glyceraldehyde acetonide according to any one of claims 1 to 3, wherein the hypochlorite is previously prepared as a corresponding aqueous hypochlorite solution, and the temperature of the oxidation reaction is 10 ℃ to 25 ℃.
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| CN1863787A (en) * | 2003-10-07 | 2006-11-15 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of (s)-glyceraldehyde acetonide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1863787A (en) * | 2003-10-07 | 2006-11-15 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of (s)-glyceraldehyde acetonide |
Non-Patent Citations (2)
| Title |
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| （S）-甘油醛缩丙酮的新合成方法;马超等;《化学研究与应用》;20111231;第23卷(第12期);第1703-1706页 * |
| 相转移催化D-甘露醇合成镇咳药左旋羟苯哌嗪;尹显洪;《化学试剂》;20011231;第23卷(第6期);第349-350页 * |
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